primary lung adenocarcinomas in children and adolescents treated for pediatric ... ·...

ORIGINAL ARTICLE

Primary Lung Adenocarcinomas in Children andAdolescents Treated for Pediatric Malignancies

Mark L. Kayton, MD,* Mai He, MD, PhD,† Maureen F. Zakowski, MD,†Andre L. Moreira, MD, PhD,† Christopher Lau, PhD,† Alexander J. Chou, MD,‡

Melinda Merchant, MD, PhD,‡ Pamela R. Merola, MD,‡ Leonard H. Wexler, MD,‡Michael P. La Quaglia, MD,* William D. Travis, MD,† and Marc Ladanyi, MD†§

Introduction: Primary lung adenocarcinoma is extremely rare in thepediatric age group. There have been anecdotal reports of lesionsthat are histologically indistinguishable from adult-type pulmonaryadenocarcinoma in young patients after treatment for nonpulmonarycancers. Herein, we present clinical, histopathologic, and moleculardata on eight such cases.Methods: Histopathologic evaluation of the tumors was performedaccording to the World Health Organization classification. Molecu-lar studies for EGFR and KRAS mutations were performed on sixpatients with sufficient material.Results: All eight patients were never smokers, four males and fourfemales. Median age at nonpulmonary cancer diagnosis was 14years (range, 3–23 years). Pulmonary adenocarcinomas were diag-nosed at a median age of 15 years (range, 10–24 years); tumors were0.1 to 2.0 cm in size and in some cases coexisted with metastasesfrom the original cancer. Retrospective review showed that in atleast three patients, the nodules were radiographically present beforechemotherapy. Of six patients whose tumors were tested for com-mon EGFR and KRAS mutations, two were positive for the formerand one for the latter. At a median follow-up of 11 months (range,2–29 months), six patients remained well without lung nodules andtwo had additional small, peripheral lung nodules that have not beenbiopsied.Conclusions: Pulmonary lesions found in young patients withpediatric cancers can be histologically indistinguishable from lungadenocarcinoma seen in adults, may display typical adenocarcino-ma-associated mutations of EGFR and KRAS, and may precede theadministration of cytotoxic chemotherapy.

Key Words: Bronchioloalveolar carcinoma, Lung cancer, Adeno-carcinoma, Secondary malignancies, Osteosarcoma, EGFR, KRAS.

(J Thorac Oncol. 2010;5: 1764–1771)

Primary adenocarcinoma of the lung is exceedingly rare inpediatric patients. In 1982, a review of the 230 pediatric

cases from the English-language literature identified only47 classifiable as “bronchogenic carcinoma.”1 Although asmall number of sporadic pulmonary adenocarcinomashave been reported since then,2–5 the preponderance havebeen found in conjunction with congenital cystic adeno-matoid malformations (CCAM) of the lung.6 –16 Beyondthis, given the scarcity of cases, it has not been possible todetermine other risk factors for pulmonary adenocarci-noma in children or adolescents.

In 1988, Travis et al.17 reported two adolescent cancerpatients who had lesions that histologically resembled adult-type bronchioloalveolar carcinoma (BAC) in the setting oftreatment for other, nonpulmonary malignancies. These lunglesions were termed “pulmonary nodules resembling bron-chioloalveolar carcinoma,” despite their identical morphol-ogy to adult-type BAC, because of the question whetherbiologically these represented true lung adenocarcinomas. Sincethat initial report, similar lesions have been described in six otherpediatric cancer patients (Supplemental Table 1, SupplementalDigital Content 1, http://links.lww.com/JTO/A37).18–23 All thepatients had been treated for other pediatric malignancies ofnonpulmonary origin. Until now, it had seemed reasonable toconsider these lesions as secondary malignancies; such aconcept is grounded in the observation that survivors ofchildhood cancer have a greater than 14-fold increase in therelative risk of developing second malignant neoplasms24 andby the recent observation of renal translocation-related car-cinomas in children after the administration of cytotoxicchemotherapy for another cancer.25 Herein, we describe thelargest series of such cases assembled to date, eight patientsbetween the age of 10 and 24 years with pulmonary lesionsindistinguishable from adult lung adenocarcinomas, includ-ing invasive tumors as well as BAC (adenocarcinoma in situ)that were detected either synchronously with, or subsequentto, treatment for primary pediatric tumors of nonpulmonaryorigin.

PATIENTS AND METHODSCases were identified in the course of clinical care or

consultation activities by the authors during the 7-year pe-riod, 2003–2009. In compliance with institutional protocols

Departments of *Surgery, †Pathology, and ‡Pediatrics, and §The HumanOncology and Pathogenesis Program, Memorial Sloan-Kettering CancerCenter, New York, New York.

Disclosure: The authors declare no conflicts of interest.Address for correspondence: Marc Ladanyi, MD, Department of Pathology,

Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY 10065. E-mail: [email protected]

Copyright © 2010 by the International Association for the Study of LungCancerISSN: 1556-0864/10/0511-1764

Journal of Thoracic Oncology • Volume 5, Number 11, November 20101764

and with guidelines of the Health Insurance Portability andAccountability Act, a waiver was obtained from the Institu-tional Review Board of Memorial Sloan-Kettering CancerCenter (MSKCC) to conduct this retrospective review. Clin-ical histories, radiologic studies, operative notes, pathologicanalyses, and medical records were evaluated.

Because each of these lesions was discovered inciden-tally in the course of lung surgery for presumed metastaticdisease, operations were conducted in keeping with publishedpractices for pediatric patients with lung metastases.26 Inparticular, lobectomy and hilar lymph node dissection werenot performed, as pulmonary lymphatic spread is not typicalfor the histologies expected to be seen in pediatrics.

Thoracotomies were performed in six of the sevencases described here, and the histopathologic findings in thewedge resection specimens were evaluated by pathologistswith special expertise in thoracic oncologic pathology(M.F.Z, A.L.M., and W.D.T.). In the one patient seen atMSKCC whose lung resection had been performed elsewhere(#2), pathology slides from an outside institution were avail-able for review.

For analysis of EGFR and KRAS mutations, pulmonarynodules from five cases (patients 3 to 7) were macrodissectedfrom formalin-fixed, paraffin-embedded sections, andgenomic DNA was extracted. Mutational analysis of EGFRwas performed as published.27 Briefly, EGFR exon 19 de-letions were detected by length analysis of polymerasechain reaction (PCR) products. EGFR exon 21 L858Rmutations were analyzed using PCR followed by Sau96Iendonuclease digestion of PCR products. The mutantEGFR L858R PCR product shows two peaks (87 bp and173 bp), whereas the digested negative control (wild type)shows only the 173 bp peak.

In addition, EGFR exon 21 L858R mutations and KRAScodons 12 and 13 mutations were also analyzed by massspectrometry-based genotyping on a Sequenom platform (SanDiego, CA), as described in detail elsewhere.28

RESULTSClinical characteristics of the patients are described in

Table 1. All were never smokers. Median age at originalcancer diagnosis was 14 years (range, 3–23 years). Medianage at the diagnosis of pulmonary adenocarcinoma was 15years (range, 10–24 years). Six of the eight patients had aprimary diagnosis of a bone sarcoma (osteosarcoma, n � 5;chondrosarcoma, n � 1); the others had Wilms’ tumor (n �1) or neuroblastoma (n � 1). Individual case summaries aregiven below. Histopathology and EGFR and KRAS muta-tional status are summarized in Table 2. A total of six BACswere found in five patients and five invasive adenocarcino-mas in four patients. One patient had two BACs, one patienthad two invasive adenocarcinomas, and one had both a BACand an invasive adenocarcinoma. The three tumors thatshowed EGFR or KRAS mutations were adenocarcinomaswith an invasive growth pattern.

Case 1A 7-year-old boy was diagnosed with stage IV Wilms’

tumor and was treated with right radical nephrectomy, regi-

men DD-4A (vincristine, dactinomycin, and doxorubicin),and 1200 cGy whole lung irradiation. Five years later, pul-monary relapse was diagnosed, and a fine needle aspirationconfirmed malignant cells. He received chemotherapy ac-cording to Stratum C of the National Wilms’ Tumor Study-5consisting of cyclophosphamide, etoposide, and carboplatin.Thoracoscopic lung resection confirmed metastatic Wilms’tumor. During cycle 2 of maintenance, he was switched to aregimen of oral cyclophosphamide and oral etoposide. Com-puted tomographic (CT) imaging (6 years after initial diag-nosis) showed possible progression in the lung, and he wasreferred to us for thoracotomy (Figure 1A). At surgery, allsuspicious nodules were removed, including a 0.8-cm focusof metastatic Wilms’ tumor and two separate foci of BAC,each measuring 1 mm (Figures 1B, C). No further surgerywas carried out. At 11 months after thoracotomy, the patientdeveloped radiologic evidence of a solitary, enlarging, 6-mmlung nodule, the histology of which is not known.

Case 2A 3-year-old girl received multiagent chemotherapy for

an intermediate-grade, stage 3 neuroblastoma according toPediatric Oncology Group #9244 using combination vincris-tine, cisplatin, etoposide, and cyclophosphamide alternatingwith vincristine, carboplatin, etoposide, and cyclophospha-mide. This was changed owing to insufficient response tovincristine, doxorubicin, and cyclophosphamide, followed byifosfamide and etoposide; and finally she received topotecan(Pediatric Oncology Group #9361), but still no responses inurine catecholamines were noted. After referral to our center,gross total resection of the left adrenal mass was performed,showing ganglioneuroblastoma. She received no subsequentchemotherapy. Four years later, minute pulmonary noduleswere found. Thoracoscopic biopsy performed at an outsideinstitution was forwarded to our center for review and wasclassified as BAC. No additional treatment was rendered, anda follow-up CT scan 5 months later showed no progression inthe remaining pulmonary nodules.

Case 3A 19-year-old man was diagnosed with osteosarcoma

of the right proximal humerus. Calcified, subcentimeter lungnodules were seen at diagnosis. He received combinationtherapy with cisplatin, doxorubicin, and high-dose methotrex-ate. Seven months into treatment, he underwent thoracotomywith eight wedge resections. No osteosarcoma was found,and the majority of the specimens proved to be minute foci ofbenign lamellar bone, consistent with metaplastic ossifica-tion. One wedge resection contained a 0.25-cm nodule ofBAC. No additional chest surgery was performed. At 29months of follow-up since lung surgery, the patient remainedwell; a small number of tiny, highly calcified nodules wereseen on chest CT that have been stable in size and appearanceover 2 years and were thought to represent additional foci ofbenign ossification.

Case 4An 18-year-old man presented with a mass of the right

iliac bone and multiple subcentimeter pulmonary nodules.

Journal of Thoracic Oncology • Volume 5, Number 11, November 2010 Primary Lung Adenocarcinomas in Pediatric Age Group

Copyright © 2010 by the International Association for the Study of Lung Cancer 1765

Biopsy of the pelvic mass showed high-grade osteosarcomawith chondroblastic elements. He received combination cis-platin, doxorubicin, high-dose methotrexate, and pamidronateaccording to an in-house osteosarcoma protocol. At thoracot-omy 5 months after diagnosis, six suspicious nodules wereresected. None showed osteosarcoma; one was a focus ofBAC measuring 0.26 cm. Without subsequent surgical inter-vention, the patient has developed no new or progressivedisease 20 months after thoracotomy.

Case 5A 23-year-old woman was diagnosed with high-grade

osteosarcoma, osteoblastic type, of the proximal humerus.Chest CT at diagnosis showed a pulmonary nodule (Figure2A). She received combination cisplatin, doxorubicin, and

high-dose methotrexate. Thoracotomy was performed 8months into treatment, with wedge resection of the rightmiddle lobe nodule showing a 0.6 cm, well-differentiated,acinar-type adenocarcinoma of the lung (Figures 2B–D).Molecular analysis revealed the tumor to be positive forEGFR exon 21 L858R mutation by both the PCR/restrictionenzyme assay and Sequenom genotyping (Figure 2E). Nofurther surgical therapy was performed, and the patient has noevidence of disease with 11 months of follow-up sincethoracotomy.

Case 6An 11-year-old girl presented with a lytic lesion of the

distal femur, biopsy of which showed high-grade osteosar-coma, osteoblastic type. Lung lesions were present on CT

TABLE 1. Clinical Characteristics, Treatments, and Temporal Relationship Between Pulmonary Adenocarcinoma,Chemotherapy, and Radiotherapy of Patients

PatientNo.

Primary OncologicDiagnosis

Age at PrimaryDiagnosis Sex

Age atThoracotomy

Pulmonary AdenocarcinomaPreceeded or Followed

Cancer Therapy?

PriorChemotherapeutic

AgentsPulmonaryIrradiation

1 Wilms’ tumor 7 M 13 Unknown Actinomycin-D 1200 cGy

Vincristine

Doxorubicin

Carboplatin

Etoposide

Cyclophosphamide

2 Neuroblastoma 3 F 10a Followed Vincristine None

Cyclophosphamide

Cisplatin

Carboplatin

Doxorubicin

Etoposide

Ifosphamide

Topotecan

3 Osteosarcoma 19 M 20 Unknown Cisplatin None

Doxorubicin

High-dose methotrexate

4 Osteosarcoma 18 M 19 Preceded Cisplatin None

Doxorubicin


Pamidronate

5 Osteosarcoma 23 F 24 Preceded Cisplatin None

Doxorubicin


6 Osteosarcoma 11 F 12 Preceded Cisplatin None

Doxorubicin


L-MTP-PE

7 Chondrosarcoma 14 F 15 Unknown Vincristine None

Doxorubicin

Cyclophosphamide

Ifosfamide

Etoposide

8 Osteosarcoma 14 M 14 Preceded COG AOST0121 None

a Underwent thoracoscopic biopsy at outside institution.L-MTP-PE, liposomal muramyltripeptide phosphatidylethanolamine; COG, Children’s Oncology Group.

Kayton et al. Journal of Thoracic Oncology • Volume 5, Number 11, November 2010

Copyright © 2010 by the International Association for the Study of Lung Cancer1766

scanning at diagnosis. She was treated with combinationtherapy using cisplatin, doxorubicin, and high-dose metho-trexate. She also received liposomal muramyltripeptide phos-phatidylethanolamine. At thoracotomy, the radiographicallyidentified nodule in the left upper lobe was resected andfound to be a 5-mm focus of moderately differentiated ade-nocarcinoma, mixed subtype, with acinar and nonmucinousbronchioloalveolar patterns. Two nodules were found in theleft lower lobe that had not been detected radiographically: a3-mm acinar subtype adenocarcinoma, and separately, a1.5-mm focus of metastatic osteosarcoma. The upper lobeadenocarcinoma was tested for EGFR and KRAS mutationsand found to be negative for both. No additional surgery wascarried out for the pulmonary adenocarcinomas, but staged,contralateral thoracotomy was performed (in keeping withour practice to rule out osteosarcoma metastatic to the otherlung). The contralateral lung was free of both osteosarcomaand adenocarcinoma. She has no evidence of disease 8months after the initial thoracotomy.

Case 7A 14-year-old girl presented with a 17-cm mass of the

tibia and a simultaneously diagnosed solitary pulmonary nodule.Biopsy of the tibial lesion showed mesenchymal chondrosar-coma. Systemic therapy was administered using combinationvincristine, doxorubicin, cyclophosphamide, ifosfamide, andetoposide. Wedge resection of the previously identified lungnodule was performed, revealing metastatic chondrosarcoma. Atthoracotomy, the discovery of additional nodules, not identifiedon preoperative imaging, prompted the performance of addi-tional wedge resections. Findings included one focus of adeno-carcinoma in the right lower lobe, of mixed subtype withpapillary and bronchioloalveolar patterns, and a separate 2-mmBAC-like nodule (Figure 3A, B). The focus of mixed typeadenocarcinoma of the right lower lobe was positive for theKRAS codon 12 G3V mutation by Sequenom genotyping(Figure 3C). No additional surgery was carried out. With 11months of follow-up, she remained free of disease.

TABLE 2. Histology and Molecular Pathology of Lung Lesions

Patient No. Histopathology EGFR KRAS

1 Metastatic Wilms’ tumor n/a n/a

Bronchioloalveolar carcinomaa (2 foci of 0.1 cm each)

2 Bronchioloalveolar carcinoma (�0.5 cm) n/a n/a

3 Solitary focus of bronchioloalveolar carcinoma (0.25 cm) Negative Negative

Multiple foci of benign metaplastic ossification in lung

4 Bronchioloalveolar carcinoma (0.26 cm) Negative Negative

5 Well-differentiated, acinar-type adenocarcinoma (0.6 cm) L858R mutation Negative

6 Moderately differentiated adenocarcinoma, mixed subtype, with acinar and nonmucinousbronchioloalveolar patterns (0.5 cm)

Negative Negative

Adenocarcinoma, acinar subtype (0.3 cm)

Metastatic osteosarcoma (0.15 cm)

7 Adenocarcinoma, mixed subtype with papillary and bronchioloalveolar patterns (0.2 cm) Negative G12V mutation

Bronchioloalveolar carcinoma (0.2 cm) in adenocarcinoma

Metastatic mesenchymal chondrosarcoma (0.6 cm)

8 Moderately differentiated adenocarcinoma, mixed subtype, predominantly acinar andpapillary (2.0 cm)

Exon 19 deletion inadenocarcinoma

Not done

Metastatic osteosarcoma (0.3 cm)

a Bronchioloalveolar carcinoma is currently called adenocarcinoma in situ in the new classification.32

n/a, specimen insufficient or unavailable for molecular study.

FIGURE 1. Case 1. A, Computed tomographic (CT) image of new lung nodule (arrow) that prompted thoracotomy. B and C,Bronchioloalveolar carcinoma of 1 mm showing crowded cuboidal to columnar cells growing along alveolar walls in a lepidicfashion, with cellular stratification, overlapping of nuclei, and coarse nuclear chromatin (hematoxylin and eosin; original mag-nifications, 20� and 40�).



Case 8A 14-year-old boy was diagnosed with high-grade

osteosarcoma of the right femur. A PET scan at diagnosisshowed, in addition to the primary lesion in the right lowerextremity, a 2.7-cm left lower lobe hypermetabolic mass inthe lung that was considered likely to be a metastasis. Heunderwent limb salvage surgery and treatment according toCOG protocol AOST0121 was initiated. At 3 months, a chest

CT revealed the left lower lobe somewhat reduced in size (1.6cm) as well as some small nodules in the lingual and rightlung base. Thoracotomy was performed 5 months into treat-ment, with wedge resection of two lingular nodules and leftlower lobectomy. The lingular lesions were a calcified noduleand a nodule with osteoid, consistent with treated osteosar-coma. The left lower lesion was a 2.0 cm, predominantlyacinar-type adenocarcinoma of the lung (Figure 4) immuno-

FIGURE 2. Case 5. A, Suspicious density seen on CT scan in the right middle lobe of the lung at the time of diagnosis of os-teosarcoma of the humerus. B and C, Invasive adenocarcinoma of the right middle lobe of the lung. Note the presence of in-vasive glands with fibrotic stroma and sharp demarcation between the tumor cells and the normal pulmonary parenchyma(hematoxylin and eosin; original magnifications, 10� and 40�). D, Immunohistochemical stain for TTF-1. This photomicro-graph shows that the invasive glands are positive for TTF-1, thus confirming a pulmonary origin for this adenocarcinoma. E,Mass spectrometry-based genotyping for EGFR exon 21 L858R mutation on Sequenom platform confirming the presence ofL858R mutation. The germline peak is indicated by an asterisk and the mutant peak by an arrow. CT, computed tomography;TTF, thyroid transcription factor-1.

FIGURE 3. Case 7. A, Right lower lobe adenocarcinoma, mixed subtype with papillary and bronchioloalveolar patterns (he-matoxylin and eosin; original magnification, 40�). B, Bronchioloalveolar carcinoma-like nodule in the right middle lobe notseen on preoperative CT scan (hematoxylin and eosin; original magnification, 40�). C, Sequenom genotyping assay showingthe presence of G 3 T mutation at position 35 in KRAS codon 12 (G12V mutation) in the mixed-type adenocarcinoma of theright lower lobe. The germline peak is indicated by an asterisk and the mutant peak by an arrow. CT, computed tomography.



reactive for thyroid transcription factor-1 and CK7 and neg-ative for CDX2 and CK20. Molecular analysis revealed thelung adenocarcinoma to be positive for EGFR exon 19deletion. The patient is at only 2 months postthoracotomy.

EGFR and KRAS MutationsTable 2 summarizes the findings with respect to EGFR

and KRAS mutations. Of the six patients whose tumors weretested, three were found negative for the common mutationsof both EGFR and KRAS. The adenocarcinomas in patients 5and 8 were positive for mutation of EGFR. In patient 7, theadenocarcinoma showed a G12V mutation in KRAS.

Temporal Relationship to ChemotherapyTemporal relationship between the administration of

chemotherapy and the finding of adenocarcinoma in the lungis shown in Table 1. In at least four of the eight patients,pulmonary nodules that later proved to be adenocarcinomawere detected by imaging before the administration of poten-tially mutagenic chemotherapy.

Clinical Follow-UpAdditional surgery related to the pulmonary adenocar-

cinomas, such as lobectomy or hilar lymph node dissection,was not carried out in any of the patients. Additional chemo-therapy, beyond the substantial multiagent regimens alreadyprescribed for the nonpulmonary primary cancers, was notadministered. Median duration of follow-up is 11 months(range, 5–29 months) (Table 3). During this follow-up, twopatients had persistent or recurrent radiographic evidence ofsmall lung nodules (histology unknown). Five patients re-mained free of disease with respect to both primary tumors.

DISCUSSIONOur analysis of this series indicates that the tumors

previously described as BAC-like nodules found in pediatric

cancer patients are (1) adenocarcinomas with a spectrum ofBAC (adenocarcinoma in situ) and invasive histologic pat-terns and (2) may be present before administration of che-motherapy for the underlying malignancy and therefore arenot always or necessarily secondary malignancies, as hadbeen previously believed. Specifically, patients 4, 5, 6, and 8had radiographic evidence of pulmonary nodules at the timeof their original cancer diagnosis before any treatment. In twopatients, these nodules proved to be adenocarcinomas, and intwo cases, there was adenocarcinoma coexisting with lungmetastases from osteosarcoma. The observation of eightyoung patients with incidental pulmonary adenocarcinomasraises the possibility that the contemporaneous presence of aprimary pediatric malignancy and pulmonary adenocarci-noma may reflect more than coincidence.

Our study clearly documents that invasive patterns ofadenocarcinoma occur in the setting of pediatric cancer pa-tients in addition to BAC/adenocarcinoma in situ. Three ofthe seven patients had areas of invasion in addition to theBAC/adenocarcinoma in situ. How to properly classify thelung tumors with BAC/adenocarcinoma in situ histology inyoung cancer patients has been problematic since their orig-inal description in 1988, because of their noninvasive growthpattern, their presentation as incidental findings, and theyoung age of the patients. For these reasons in 1988, we(W.D.T.) were reluctant to call these tumors BAC and qual-ified the terminology for these cases as “BAC-like nodule.”However, in 1995, it was recognized that patients with smallsolitary adenocarcinomas with a pure BAC histology in theabsence of any invasion have a 100% 5-year survival.29 Thisled to a strict redefinition of the use of the term BAC by 1999World Health Organization classification as a noninvasivetumor with pure lepidic growth, and this concept was main-tained in the 2004 classification.30,31 Furthermore, the excel-lent survival for small solitary BACs has been validated inmultiple subsequent studies, so these tumors are currentlybeing proposed to be called “adenocarcinoma in situ” in thenext classification of lung adenocarcinoma.32 Notably, how-ever, we found invasive patterns of lung adenocarcinoma infour of the eight patients in this study.

FIGURE 4. Case 8. Left lower lobe adenocarcinoma, mixedsubtype with predominant acinar pattern (hematoxylin andeosin; original magnification, 40�). This tumor contained anEGFR mutation (exon 19 deletion) (see text). EGFR, epider-mal growth factor receptor.

TABLE 3. Clinical Outcomes

PatientNo.

Follow-UpSince

Thoracotomy(mo)

AdditionalTreatment for

PulmonaryAdenocarcinoma

Disease Statusof Primary

Tumor

Disease Statusof Pulmonary

Adenocarcinoma

1 11 None AWD AWDa

2 5 None NED AWD

3 29 None NED NED

4 20 None NED NED

5 11 None NED NED

6 8 None NED NED

7 11 None NED NED

8 2 None NED NED

a Patient 1 has a solitary enlarging lung nodule at last follow-up, the histology ofwhich is not yet determined.

AWD, alive with disease, NED, no evidence of disease.



Pediatric cancer patients undergo lung imaging andthoracotomy at a rate vastly exceeding that of healthy chil-dren, so it may be argued that incidentally found lung lesionssuch as these may have a different natural history from usualadult lung cancer. However, incidental pulmonary adenocar-cinomas have so far not been reported among children un-dergoing workup and surgery for benign etiologies such astrauma, bleb disease, or empyema. There is, however, awell-established association between CCAM and pulmonaryadenocarcinoma. However, CCAM-associated adenocarcino-mas are typically mucinous lesions and likely stem from adifferent underlying molecular pathway. Mucinous BACs areassociated with higher frequencies of KRAS mutations com-pared with nonmucinous tumors,33 and mucinous carcinomasseen in association with CCAMs have been shown to exhibitloss of heterozygosity at the p16INK4 locus.34 Such lesionsshould be contrasted with the nonmucinous lesions exhibitedby the patients in this series, as well as by most of the pediatriccancer patients previously reported to have developed pulmo-nary adenocarcinoma (Supplemental Table 1, SupplementalDigital Content 1, http://links.lww.com/JTO/A37). The coexist-ence of primary pediatric malignancies and early pulmonaryadenocarcinomas as seen here may reflect the presence of anunderlying germline predisposition or a common carcino-genic exposure. Additional cases may help to define this, butwe should note that none of the patients had family historiessuggestive of known familial cancer syndromes. In this re-gard, a locus associated with increased risk of lung cancer innever smokers has recently been reported.35

To our knowledge, mutations in EGFR or KRAS havenot been previously documented in pediatric pulmonary ad-enocarcinoma. The mutational analysis presented here pro-vides a starting point for elucidating the genetic alterationsdriving lung neoplasia in this clinical setting. Two of theeight with predominantly acinar histology displayed theEGFR mutations, and another mixed subtype adenocarci-noma showed the KRAS G12V mutation. All three of thesetumors had an invasive growth pattern. This mutation rate isnot statistically different from the incidence of such muta-tions among adult North American lung cancer patients,where 20% of lung adenocarcinomas harbor mutations ofEGFR36 and about 25 to 30% contain KRAS mutations.37,38

The EGFR mutations have a negative association with smok-ing, whereas KRAS G12V lacks a clear negative or positiveassociation with smoking.39 The presence of these mutations,in addition to the histology, provides further evidence that thesetumors are clonal neoplasms, rather than reactive atypical pneu-mocyte proliferations. Finally, Park et al40 recently reported twoadolescents with lung adenocarcinoma without a prior or con-current pediatric cancer who both died of their disease.

After surgical resection, the appropriate follow-uptreatment for an incidentally discovered, subcentimeter pul-monary adenocarcinoma is not defined in pediatrics. Theprinciples in surgery for lung cancer are founded on data fromadults with tumors large enough to be detected on chestradiographs, rather than the minute tumors found by CTscanning or by palpation at the time of thoracotomy.41,42 Thesurgical management of incidentally discovered pulmonary

adenocarcinomas less than 2 cm in size has been significantlyrevisited in recent years by Rusch and others, with an em-phasis on sublobar resection.43–49 Despite the persistence ofpulmonary nodules of unknown histology in two of ourpatients, we did not observe definite malignant behavior suchas recurrence or metastases in any of our cases.

Seven of the eight patients presented here were com-prehensively discussed at a multidisciplinary tumor board. Ineach case, the consensus was reached that preservation ofpulmonary parenchyma and of lung function were overridingpriorities, especially in light of the potential need for addi-tional pulmonary metastatectomies in the future, given thesepatients’ underlying high-grade malignancies. Consequently,we have chosen close surveillance and have specificallyavoided repeat thoracotomies for lobectomies or hilar lymphnode dissections. No additional chemotherapy was thought tobe warranted. Most of the patients were still in the process ofreceiving aggressive combination chemotherapy regimens fortheir primary tumors when the diagnosis of pulmonary ade-nocarcinoma was made. Continued follow-up and molecularstudies will be needed to more definitively comment on thesuccess of this approach.

ACKNOWLEDGMENTSSupported by the Anbinder Fund (MSKCC Sequenom

facility) and National Cancer Institute (P01-CA129243 to M.L.).The authors thank Dr. Paul Meyers for encouraging the

compilation of this series for publication; Dr. Marian Flem-ing (Banner Desert Medical Center, Mesa, AZ) for submittingone of the cases; and Dr. Greg Riely for helpful comments.They also thank Dr. Laetitia Borsu for assistance with Se-quenom assays.

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